ES2959952T3 - Compounds for the treatment of CMTN - Google Patents

Abstract

Tinostamustine or a pharmaceutically acceptable salt thereof is provided for use in the treatment of triple negative breast cancer (TNBC) to a patient in need thereof. (Automatic translation with Google Translate, without legal value)

Description

DESCRIPTION

Compounds for the treatment of CMTN

Technical field

The present invention relates to compositions for the treatment of cancer, particularly triple negative breast cancer (TNBC).

Background of the invention

Cancer is one of the deadliest diseases. Cancer is a condition in which cells in a part of the body experience uncontrolled growth. According to the latest data from the American Cancer Society, there will be an estimated 1.69 million new cases of cancer in the United States in 2017.

Cancer is the second leading cause of death in the United States (second only to heart disease) and will claim more than 601,000 lives in 2017. In fact, the average lifetime risk of developing cancer is estimated to be 40.8 % for American men and 37.5% for American women. Therefore, cancer constitutes a major public health burden and represents a significant cost in the United States. These figures are mirrored elsewhere in most countries around the world, although the types of cancer and the relative proportions of the population suffering from cancers vary depending on many different factors, such as genetics and diet.

For decades, surgery, chemotherapy and radiation were the established treatments for various cancers. Patients usually receive a combination of these treatments depending on the type and extent of their disease. But chemotherapy is the most important option for cancer patients when surgical treatment (that is, removal of diseased tissue) is impossible. Although surgery is sometimes effective in removing tumors located in certain sites, for example, in the breast, colon, and skin, it cannot be used to treat tumors located in other areas, such as the spine, or the treatment of disseminated hematological cancers, including cancers of the blood and blood-forming tissues (such as bone marrow). Such cancers include multiple myeloma, lymphoma, and leukemia. Radiotherapy involves exposing living tissue to ionizing radiation that causes death or damage to the exposed cells. Side effects of radiation therapy may be acute and temporary, while others may be irreversible. Chemotherapy involves the interruption of cell replication or cell metabolism. It is most commonly used in the treatment of breast, lung and testicular cancer. One of the main causes of chemotherapy failure is the development of drug resistance by cancer cells, a serious problem that can lead to recurrence of the disease or even death. Therefore, more effective cancer treatments are needed.

Solid tumors are a mass of abnormal tissue that usually does not contain cysts or fluid areas. Solid tumors can be benign (non-cancerous) or malignant (cancerous). The different types of solid tumors are named by the type of cells that form them. Examples of solid tumors are carcinomas and sarcomas. The four most common cancers occurring worldwide are all solid tumors, that is, lung, breast, bowel and prostate cancer. These four cancers with solid tumors account for about 4 in 10 of the cancers diagnosed worldwide.

According to the National Cancer Institute, there were an estimated 252,170 new cases and 40,610 deaths from breast cancer (women only) in the US in 2017.

Breast cancer is the most common non-skin cancer in women in the US, with an estimated 61,000 cases of in situ disease and 246,660 cases of invasive disease in 2016. Consequently, fewer than one in six women diagnosed with breast cancer dies from the disease. By comparison, it is estimated that approximately 71,280 American women will die from lung cancer in 2017. Men account for 1% of breast cancer cases and breast cancer deaths.

Breast cancer is not one form of cancer, but rather consists of many different subtypes of cancer. These subtypes of breast cancer are typically diagnosed based on the presence (or lack of) three receptors: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2). About 10-20% of breast cancers are negative for estrogen and progesterone receptors and have amplification of the HER2 gene, and are known as triple-negative breast cancer (TNBC). TNBC tends to be more aggressive than other types of breast cancer and is more likely to metastasize or recur.

Given the prevalence of solid tumors, including breast cancer, there is therefore a need for new effective chemotherapeutic treatments.

In WO-A-2010/085377, the compound of formula I is disclosed below. It is an innovative dual-function alkylating HDACi fusion molecule that potently inhibits HDAC-regulated pathways.

Biological assays showed that the compound of formula I potently inhibits the HDAC enzyme (HDAC1 IC 50 of 9 nM). The compound of formula I has an INN of tinostamustine and is also known in the art as EDO-S101. It is an AK-DAC (a breakthrough alkylating deacetylase molecule) that, in preclinical studies, has been shown to simultaneously improve access to DNA strands within cancer cells, their breakage, and blocking damage repair.

Summary of the invention

In a first aspect of the present invention, tinostamustine or a pharmaceutically acceptable salt thereof is provided for use in the treatment of triple negative breast cancer (TNBC) in a patient in need thereof, wherein:

in TNBC it is used in combination with a DNA damage response (RDA) inhibitor.

It has surprisingly been found that tinostamustine or a pharmaceutically acceptable salt thereof is particularly effective in the treatment of TNBC, with activity data showing strong sensitivity to this compound. Therefore, the present invention meets the need for a new and effective TNBC treatment. In another aspect of the present invention, tinostamustine or a pharmaceutically acceptable salt thereof is provided for use as monotherapy in the treatment of triple negative breast cancer (TNBC) in a patient in need thereof. Optionally:

TNBC is selected from: basal type 1 (BL1) subtype; I

TNBC is BRCA-1 wild type.

In another aspect of the present invention, there is provided the use of tinostamustine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of triple negative breast cancer (TNBC) in a patient in need thereof, wherein:

TNBC is selected from: basal type 1 (BL1) subtype; I

TNBC is BRCA-1 wild type.

In another aspect of the present invention, there is provided the use of tinostamustine or a pharmaceutically acceptable salt thereof as a monotherapy for the manufacture of a medicament for the treatment of triple negative breast cancer (TNBC) in a patient in need thereof. Optionally:

TNBC is selected from: basal type 1 (BL1) subtype; I

TNBC is BRCA-1 wild type.

In another aspect of the present invention, there is provided a method of treating triple negative breast cancer (TNBC) in a patient in need thereof, comprising administering to said patient an effective amount of tinostamustine or a pharmaceutically acceptable salt thereof, where:

TNBC is selected from: basal type 1 (BL1) subtype; I

TNBC is BRCA-1 wild type.

In another aspect of the present invention, there is provided a method of treating triple negative breast cancer (TNBC) in a patient in need thereof, comprising administering to said patient an effective amount of tinostamustine or a pharmaceutically acceptable salt thereof as monotherapy. Optionally:

TNBC is selected from: basal type 1 (BL1) subtype; I

TNBC is BRCA-1 wild type.

In another aspect of the present invention, there is provided a kit comprising tinostamustine or a pharmaceutically acceptable salt thereof together with instructions for treating triple negative breast cancer (TNBC) in a patient in need thereof, wherein:

TNBC is selected from: basal type 1 (BL1) subtype; I

TNBC is BRCA-1 wild type.

In another aspect of the present invention, a kit comprising tinostamustine or a pharmaceutically acceptable salt thereof is provided together with instructions for treating triple negative breast cancer (TNBC) as monotherapy in a patient in need thereof. Optionally:

TNBC is selected from: basal type 1 (BL1) subtype; I

TNBC is BRCA-1 wild type.

In a further aspect, tinostamustine or a pharmaceutically acceptable salt thereof may be administered in combination with one or more additional agents. The additional agent(s) may be DNA repair inhibitors. The additional agent(s) may be DNA damage response (RDA) inhibitors. The additional agent may be a PARp inhibitor. The PARP inhibitor may be olaparib.

When used in combination, tinostamustine or a pharmaceutically acceptable salt thereof, and said additional agent(s) may be administered concurrently, sequentially, or separately. In one embodiment, the agents are administered concurrently. In a further embodiment, the agents are administered sequentially. In a further embodiment, the agents are administered separately. In a further aspect, there is provided a combination comprising tinostamustine or a pharmaceutically acceptable salt thereof and another agent(s) selected from DNA repair inhibitors, RDA inhibitors, PARp inhibitors or olaparib.

Combinations of tinostamustine or a pharmaceutically acceptable salt thereof and other agent(s) selected from DNA repair inhibitors, RDA inhibitors, PARP inhibitors or olaparib have been found to be particularly effective in the treatment of cancers, such as TNBC, such that they hold great promise in efforts to address the problems of finding more effective cancer treatments. Tinostamustine or a pharmaceutically acceptable salt thereof, and said additional agent(s) may be administered concurrently, sequentially or separately. In one embodiment, the agents are administered concurrently. In a further embodiment, the agents are administered sequentially. In a further embodiment, the agents are administered separately.

In a further aspect, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination according to the present invention.

In a further aspect, a kit is provided comprising a combination according to the present invention and optionally instructions for treating a patient.

In a further aspect, a combination according to the present invention is provided for use as a medicament.

In a further aspect, a combination according to the present invention is provided for use in the treatment of cancer.

The following features apply to all aspects of the invention.

The cancer may be TNBC.

The CMTN subtype may be BL1.

The TNBC subtype may be wild-type BRCA-1.

TNBC can be recurrent and/or resistant.

CMTN may be resistant to platinum.

TNBC may be wild-type BRCA-1.

The cancer can be recurrent and/or resistant.

Cancer can be localized.

The cancer can be metastatic.

The cancer can be advanced.

The cancer may have progressed after at least one line of conventional therapy.

One or more additional agents may be administered in combination with tinostamustine or a pharmaceutically acceptable salt thereof.

The combination may be tinostamustine or a pharmaceutically acceptable salt thereof and another agent or agents. The additional agent may be carboplatin.

The additional agent(s) may be DNA repair inhibitors.

The additional agent(s) may be RDA inhibitors.

The additional agent(s) may be PARP inhibitors.

The PARP inhibitor may be olaparib.

Additional agents may be carboplatin and a PARP inhibitor.

DNA repair inhibitors, RDA inhibitors, PARP inhibitors, olaparib can be combined with carboplatin.

Additional agents may be carboplatin and olaparib.

Description of the drawings

Figure 1a shows an HCC1143 p13 spheroid after 48 h before starting treatment.

Figure 1b shows the residual cell viability (% solvent control) of the HCC1143 p13 spheroid model for EDO-S101 alone and in combination with carboplatin and/or olaparib after 48 h and 72 h.

Detailed description of the invention

In this application, a series of general terms and expressions are used, which should be interpreted as follows.

The compound of formula I has an INN of tinostamustine and is also known in the art as EDO-S101. The IUPAC name is 7-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)-N-hydroxyheptanamide.

"Patient" includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, deer, and the like), and non-mammals (e.g., birds, and the like).

"Pharmaceutically acceptable salts" means salts of compounds of the present invention that are pharmaceutically acceptable, as defined above, and that possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids or with organic acids. Pharmaceutically acceptable salts also include base addition salts that can be formed when the acidic protons present are capable of reacting with organic or inorganic bases. In general, such salts are prepared, for example, by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate. , trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, salicylate, tosylate, lactate, naphthalenesulfonate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts, such as, for example, ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine and basic amino acid salts.

In the present invention, the pharmaceutically acceptable salt of tinostamustine may preferably be the hydrochloride, hydrobromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, oxalate, succinate , fumarate, tartrate, tosylate, mandelate, salicylate, lactate, p-toluenesulfonate, naphthalenesulfonate salt or acetate.

It has surprisingly been discovered that tinostamustine or a pharmaceutically acceptable salt thereof shows surprising efficacy in solid tumors. In particular, tinostamustine or a pharmaceutically acceptable salt thereof has been found to be useful in the treatment of TNBC.

Breast cancer is not one form of cancer, but many different subtypes of cancer. These subtypes of breast cancer are typically diagnosed based on the presence (or lack of) three receptors: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2). About 10-20% of breast cancers are negative for estrogen and progesterone receptors and have amplification of the HER2 gene, and are known as triple-negative breast cancer (TNBC).

The absence of these receptors means that cancers are unlikely to respond to hormonal therapies, including tamoxifen, anastrozole, exemestane, letrozole and fulvestrant). Triple-negative breast cancers are also unlikely to respond to drugs that target HER2, such as trastuzumab or lapatinib.

Triple negative breast cancers also tend to be more aggressive than other types of breast cancer and are more likely to metastasize or recur. Five-year survival rates also tend to be lower for triple-negative breast cancers. For example, a 2007 study of more than 50,000 women across all stages of breast cancer found that 77% of women with triple-negative breast cancer survived at least 5 years, compared with 93% of women with other types. of breast cancer. Another study of more than 1,600 women published in 2007 determined that women with triple-negative breast cancer had an increased risk of death within 5 years of diagnosis, but not after that time period.

Triple negative breast cancer tends to be higher grade than other types of breast cancer, often scoring a grade 3 in their appearance and growth patterns.

Triple-negative breast cancer represents a heterogeneous disease and gene expression analysis has identified distinct subtypes, each displaying a unique biology: basal type (including basal type 1 (BL1) and basal type 2 (BL2) subgroups), mesenchymal (M) and luminal androgen receptor (LAR) subtypes (Lehmann et al.Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection;PLOS 1; 2016 https://doi.org/10.1371/journal. puts.0157368).

The BL1 subtype expresses high levels of genes involved in cell proliferation and the response to DNA damage. Cell lines associated with the BL1 subtype include HCC1143 (BRCA-1 wild type) and HCC1937 (BRCA-1 negative).

Given the prevalence of TNBC and resistance to current therapies, there is a need for new effective chemotherapeutic treatments.

Tinostamustine or a pharmaceutically acceptable salt has surprisingly been shown to be effective in the treatment of basal type 1 (BL1) subgroup TNBC. Additionally, tinostamustine or a pharmaceutically acceptable salt has been shown to be effective in the treatment of BRCA-1 wild-type breast cancer.

It has also been shown for the first time that tinostamustine or a pharmaceutically acceptable salt is effective as monotherapy in the treatment of TNBC.

The therapeutically effective amount of tinostamustine or a pharmaceutically acceptable salt administered to the patient is an amount that confers a therapeutic effect according to the present invention in the treated subject, with a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject provides an indication of or perceives an effect). An effective amount of tinostamustine or a pharmaceutically acceptable salt thereof according to the present invention is believed to be one wherein tinostamustine or a pharmaceutically acceptable salt thereof is included in a dosage range of 0.3 mg/m2 to 300 mg /m2 of patient body surface area or from 60 mg/m2 to 150 mg/m2 of patient body surface area. In a preferred embodiment, the dosage range is from 80 mg/m2 to 100 mg/m2 of patient body surface area.

The specific dose level therapeutically effective for any particular patient will depend on various factors, including the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, body weight, general health, gender, and diet; the time of administration, the route of administration and the rate of excretion of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the specific compound used; and similar factors well known in the medical art.

"Metastatic cancer." Cancer has the ability to spread within the body. Cancer cells can spread locally by moving into nearby normal tissue. Cancer can also spread regionally, to nearby lymph nodes, tissues, or organs. Therefore, cancer can spread to distant parts of the body. When this happens, it is called metastatic cancer (also known as stage IV cancer), and the process by which cancer cells spread to other parts of the body is called metastasis. Therefore, in metastasis, cancer cells break away from where they first formed (primary cancer), travel through the blood or lymph system, and form new tumors (metastatic tumors) in other parts of the body.

Metastatic cancer cells have characteristics like those of the primary cancer and not like the cells at the site where the cancer is found. This allows doctors to determine if a cancer is metastatic. Metastatic cancers are called the same as the primary cancer. For example, breast cancer that has spread to the lung is called metastatic breast cancer, not lung cancer. It is treated as stage IV breast cancer, not lung cancer.

Metastatic TNBC refers to a triple-negative breast cancer that has metastasized to a new location in the body. The cancer is treated as stage IV TNBC.

"Advanced cancer" is cancer that is not curable but responds to treatment. Disease-targeted therapy remains very important because it prolongs life. For terminal cancer, therapy cannot significantly prolong survival due to the progressive nature of the disease and palliative care is the main treatment option.

"Monotherapy" according to the present invention means that tinostamustine or a pharmaceutically acceptable salt thereof is administered alone as a single agent, that is, it is not administered in combination with another drug or drugs. Examples of such drugs include (but are not limited to) proteasome inhibitors, glucocorticoids and/or tyrosine kinase inhibitors. However, tinostamustine monotherapy may include radiotherapy.

“DNA repair inhibitors” and “DNA damage response (RDA) inhibitors” target the repair/response pathways of cells and are a promising therapeutic avenue in cancer therapy. An example is the class of poly(ADP-ribose) polymerase (PARP) inhibitors, including olaparib.

In embodiments of the present invention, tinostamustine is administered in combination with another agent or agents. These agents may include DNA repair inhibitors, RDA inhibitors, PARP inhibitors, olaparib, and/or carboplatin. In embodiments, the combinations may exclude proteasome inhibitors, glucocorticoids and/or tyrosine kinase inhibitors.

Suitable examples of the form of administration of tinostamustine or a pharmaceutically acceptable salt thereof include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, ocular and intranasal. Parenteral administration includes subcutaneous injections, intravenous injection, intramuscular, intrasternal or infusion techniques. Preferably, tinostamustine or a pharmaceutically acceptable salt thereof is administered parenterally and more preferably intravenously.

"BRCA-1 wild type". BRCA-1 is a gene found on chromosome 17. BRCA-1 is a human gene that produces tumor suppressor proteins. These proteins help repair damaged DNA and therefore play a role in ensuring the stability of each cell's genetic material. When any of these genes are mutated or altered, such that their protein product is not made or does not function properly, the DNA damage may not be repaired properly. As a result, cells are more likely to have additional genetic alterations that can lead to cancer. Specific inherited mutations in BRCA-1 markedly increase the risk of female breast and ovarian cancer, but have also been associated with an increased risk of several additional types of cancer. People who have inherited BRCA-1 mutations tend to get breast and ovarian cancers at younger ages than people who do not have these mutations.

A harmful BRCA-1 mutation can be inherited from a person's mother or father. Each child of a parent who carries a mutation in the gene has a 50% (or 1 in 2) chance of inheriting the mutation. The effects of BRCA-1 mutations are seen even when a person's second copy of the gene is normal.

In contrast, a person who has a BRCA-1 gene that is not mutated has a "wild-type" gene, that is, not mutated. BRCA-1 wild type means a patient who has the unmutated BRCA-1 gene.

A woman's lifetime risk of developing breast cancer is greatly increased if she inherits a harmful mutation in BRCA-1. Approximately 12% of women in the general population will develop breast cancer at some point in their lives. In contrast, a recent large study estimated that approximately 72% of women who inherit a harmful BRCA-1 mutation will develop breast cancer by the age of 80. Like women in the general population, those with harmful BRCA-1 mutations are also at high risk of developing a new primary cancer in the opposite (contralateral) breast in the years after a breast cancer diagnosis. It has been estimated that 20 years after a first breast cancer diagnosis, approximately 40% of women who inherit a harmful BRCA-1 mutation will develop cancer in the other breast. As such, patients who have a mutated BRCA-1 gene have an increased risk of developing cancer.

At the same time, the presence of mutations in the BRCA-1 gene limits the DNA repair pathways of BRCA-1 mutant tumors, making these tumors more susceptible to certain therapies, including DNA-damaging agents such as platinum agents. Consequently, patients who are BRCA-1 wild type may have a worse prognosis and outcomes.

Preferably, tinostamustine or a pharmaceutically acceptable salt thereof is administered intravenously to the patient in need thereof at a dosage level for the patient in need thereof of 0.3 mg/m2 up to 300 mg/m2 body surface area. of the patient.

Preferably, tinostamustine or a pharmaceutically acceptable salt thereof is administered intravenously to the patient in need thereof at a dosage level for the patient in need thereof of 60 mg/m2 up to 150 mg/m2 body surface area of the patient. .

Preferably, tinostamustine or a pharmaceutically acceptable salt thereof is administered intravenously to the patient in need thereof at a dosage level for the patient in need thereof of 80 mg/m2 up to 100 mg/m2 body surface area of the patient. .

It has been discovered that, in embodiments of the present invention, tinostamustine or a pharmaceutically acceptable salt thereof or the medicament comprising the same can be preferably administered to a patient in need thereof on days 1, 8 and 15 of a cycle of 28-day treatment or days 1 and 15 of a 28-day treatment cycle.

Preferably, tinostamustine or a pharmaceutically acceptable salt thereof is administered on days 1 and 15 of a 28-day treatment cycle.

It has been discovered that, in embodiments of the present invention, tinostamustine or a pharmaceutically acceptable salt thereof or a medicament comprising the same may be preferably administered to a patient in need thereof over an infusion time of 60 minutes; or an infusion time of 45 minutes; or an infusion time of 30 minutes.

Preferably, tinostamustine or a pharmaceutically acceptable salt thereof is administered over an infusion time of 60 minutes.

In a preferred embodiment, tinostamustine or a pharmaceutically acceptable salt is administered to the patient in need thereof at a dosage level of 80 mg/m2 to 100 mg/m2 body surface area of the patient, on days 1 and 15 of a cycle. 28-day treatment, for an infusion time of 60 minutes.

In embodiments of the present invention, a kit comprising tinostamustine or a pharmaceutically acceptable salt thereof or a medicament comprising the same is provided along with instructions.

The instructions may advise administration of tinostamustine or a pharmaceutically acceptable salt thereof depending on variables such as the status of the solid tumors being treated; the patient's age, body weight, general health, gender, and diet; the time of administration, the route of administration and the rate of excretion of the specific compounds used; the duration of treatment; the drugs used in combination or simultaneously with the specific compounds used; and similar factors well known in the medical art.

In a further embodiment of the present invention, the patient in need of such treatment receives radiotherapy with (including before, during or after) treatment of the solid tumor with tinostamustine or a pharmaceutically acceptable salt thereof. In embodiments of the present invention, the patient is treated with tinostamustine or a pharmaceutically acceptable salt thereof and radiotherapy. Preferably, the patient receives radiotherapy treatment prior to treatment with tinostamustine or a pharmaceutically acceptable salt thereof. Radiotherapy can be administered at a dose of 1 to 5 Gy for 5-10 consecutive days and preferably 2 Gy for 5-10 consecutive days.

In a further embodiment of the present invention, the patient in need of such treatment receives radiotherapy before or after treatment of solid tumors with tinostamustine or a pharmaceutically acceptable salt thereof. Preferably, the patient receives radiotherapy treatment prior to treatment with tinostamustine or a pharmaceutically acceptable salt thereof. Radiotherapy can be administered at a dose of 1 to 5 Gy for 5-10 consecutive days and preferably 2 Gy for 5-10 consecutive days.

When intended for oral administration, tinostamustine or a pharmaceutically acceptable salt thereof or the medicament comprising it may be in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included in the forms considered in this document either as a solid or as a liquid.

Tinostamustine or a pharmaceutically acceptable salt thereof or a medicament comprising it can be prepared for administration using a methodology well known in the pharmaceutical art. Examples of suitable pharmaceutical formulations and carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.

As a solid composition for oral administration, tinostamustine or a pharmaceutically acceptable salt thereof may be formulated in the form of a powder, granule, compression formed tablet, pill, capsule, chewing gum, wafer or similar forms. Said solid composition normally contains one or more inert diluents or carriers. Any inert excipient that is commonly used as a carrier or diluent can be used in the compositions of the present invention, such as sugars, polyalcohols, soluble polymers, salts and lipids. Sugars and polyols that can be used include, without limitation, lactose, sucrose, mannitol and sorbitol. Illustrative soluble polymers that can be used are polyoxyethylene, poloxamers, polyvinylpyrrolidone and dextran. Useful salts include, without limitation, sodium chloride, magnesium chloride and calcium chloride. Lipids that can be used include, without limitation, fatty acids, fatty acid esters of glycerol, glycolipids and phospholipids.

Additionally, one or more of the following may be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, corn starch and the like; lubricants such as magnesium stearate; emollients such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.

When the compositions of tinostamustine or a pharmaceutically acceptable salt thereof are in capsule form (for example, a gelatin capsule), it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol, cyclodextrin or an oil. fatty.

Compositions of tinostamustine or a pharmaceutically acceptable salt thereof may be in liquid form, for example, an elixir, syrup, solution, emulsion or suspension. The liquid may be useful for oral administration or for administration by injection. When intended for oral administration, compositions of tinostamustine or a pharmaceutically acceptable salt thereof may comprise one or more of a sweetening agent, preservatives, dye/colorant, and an aroma enhancer. In compositions of tinostamustine or a pharmaceutically acceptable salt thereof for administration by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may also be included.

The preferred route of administration is parenteral administration including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intranasal, intracerebral, intraventricular, intrathecal, intravaginal or transdermal. The preferred mode of administration is left to the discretion of the physician and will depend in part on the site of the medical condition (such as the site of the cancer). In a more preferred embodiment, tinostamustine or a pharmaceutically acceptable salt thereof or the medicament comprising it is administered intravenously.

Liquid forms of tinostamustine or a pharmaceutically acceptable salt thereof or the drug comprising it, may be solutions, suspensions or other similar forms, and may also include one or more of the following: sterile diluents such as water for injection, solution saline, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono- or diglycerides, polyethylene glycols, glycerin or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; and tonicity adjusting agents such as sodium chloride or dextrose. The parenteral combination or composition may be filled into an ampoule, a disposable syringe, or a multidose vial made of glass, plastic, or other material. Physiological saline is a preferred adjuvant.

Tinostamustine or a pharmaceutically acceptable salt thereof or the medicament comprising it can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings and preferably by bolus.

Examples of compositions comprising tinostamustine or a pharmaceutically acceptable salt thereof are disclosed in WO2013/040286.

The present invention encompasses combinations of tinostamustine or a pharmaceutically acceptable salt and a DNA repair inhibitor.

The present invention encompasses combinations of tinostamustine or a pharmaceutically acceptable salt and a DNA damage response (RDA) inhibitor.

The present invention encompasses combinations of tinostamustine or a pharmaceutically acceptable salt and a PARP inhibitor.

The PARP inhibitor may be olaparib.

Carboplatin may also be administered together with a DNA repair inhibitor, an RDA inhibitor, a PARP inhibitor, or olaparib.

In one embodiment of the combination of the present invention, tinostamustine or a pharmaceutically acceptable salt thereof and an additional agent(s) are adapted for administration concurrently, sequentially or separately. Preferably, the tinostamustine or a pharmaceutically acceptable salt thereof and the additional agent(s) are adapted for administration concurrently.

The molar ratio between another agent and tinostamustine or a pharmaceutically acceptable salt thereof in the combination of the present invention is typically 1:2000 to 2000:1.

The additional agent may be a DNA repair inhibitor, an RDA inhibitor, a PARP inhibitor, olaparib.

It has surprisingly been discovered that combinations comprising tinostamustine or a pharmaceutically acceptable salt thereof and another agent are synergistic combinations. In other words, the potency of the combinations has been measured with the Calcusyn computer program (biosoft, Ferguson, M<o>, <USA), which is based on the Chou Talay method (Chouet al., Adv. Enzyme Regul.,22, 27-55 (1984)), which calculates a combination index (CI) with the following interpretation:

IC 1 > 1: antagonistic effect, Cl=1: additive effect and IC < 1 synergistic effect.

The present invention will be further understood by consideration of the following non-limiting examples.

Examples

In the following examples, tinostamustine is called EDO-S101.

EDO-S101 can be prepared as described in example 6 of WO-A-2010/085377.

Example 1 - EDO-S101 activity in a triple negative breast cancer spheroid model

Materials and methods

The activity of EDO-S101 alone and in combination was evaluated in triple-negative breast cancer cell lines using a spheroid model.

EDO-S101 and control compounds

• EDO-S101 was provided by EDO MundiPharma and was synthesized as described in example 6 of WO-A-2010/085377.

• Carboplatin was purchased from Sigma.

• Paclitaxel was purchased from Sigma.

• Olaparib was purchased from Sigma.

Test system

The Spherotech CMTN cell line that forms multicellular spheroids was prepared for the cell line shown in Table 1.

Table 1

New triple-negative breast cancer samples were obtained once the patient's individual informed consent was obtained. Patients were recruited after clinical diagnosis and before starting chemotherapy.

Heterotypic tumor spheroids were prepared from individual primary breast cancer tissue. Tumor samples were mechanically and enzymatically digested using an enzyme cocktail (Roche, Penzberg Germany), cell viability was determined using trypan blue exclusion test, and spheroids were seeded at a cell density of 50,000 using an overlay method. modified liquids. After 48 hours in cell culture under normal conditions, successful spheroid formation was documented photographically before starting treatment.

Spheroids were treated with EDO-S101 (5 μM, 10 μM) alone and in combination with carboplatin and/or the PARP inhibitor olaparib (Table 2) for different time periods (48, 72 h). Solvent controls and an untreated control (medium) were used under the same culture conditions. The treatment efficacy of all drugs was analyzed with a standard ATP assay.

Table 2

The results of the experiments are shown in tables 3a and 3b below. Results are the average of six replicates per treatment based on ATP assay results.

continuation

Table 3a

Table 3b

Figure 1a shows an HCC1143 p1348 spheroid h after plating and before starting treatment. Figure 1b shows the residual cell viability (% solvent control) of the HCC1143 p13 spheroid model after treatment with EDO-S101 alone and in combination with carboplatin and/or olaparib after 48 h and 72 h. HCC1143 cells are of the BL1 triple-negative breast cancer subtype.

After 48 hours, treatment with EDO-S101 (5 pm and 10 pm) alone demonstrated the greatest reduction in cell viability (86% and 57% residual cell viability respectively) compared to either of the control agents (carboplatin , paclitaxel, olaparib, or combinations thereof) ranging between 85 and 118%. Treatment with 10 pm EDO-S101 revealed a pronounced reduction in cell viability activity against HCC1143 cells. The most pronounced reduction in cell viability (53% residual cell viability) was observed in spheroids treated with EDO-S101 (5 pm)+Ola.

After 72 h of treatment with EDO-S101 (5 pM and 10 pM) as monotherapy, greater activity against spheroid cell viability was observed (80% and 77% residual cell viability, respectively) compared to the negative control . Additionally, EDO-S101 monotherapy was more effective than treatment with paclitaxel, carboplatin, C+Ola, or P+Ola, but was less effective than Ola alone (62% residual cell viability). However, EDO-S101 (5|jM and 10|jM) Ola (45% and 48% residual cell viability respectively) demonstrated improved efficacy over Ola as monotherapy, as did EDO-S101 (5jM and 10jM )+Ola+C (58% and 52% residual cell viability, respectively). Therefore, EDO-S101 demonstrated greater efficacy against HCC1143 cell viability compared to paclitaxel, carboplatin, olaparib, or any combination thereof. Figures 1a and 1b demonstrate that EDO-S101 only has activity against CMTN. The figures also show that EDO-S101 in combination with other anti-cancer drugs also demonstrates activity against TNBC. This is shown in the examples in relation to:

- EDO-S101 plus the platinum agent cisplatin;

- EDO-S101 plus the PARP inhibitor olaparib;

- EDO-S101 plus cisplatin and olaparib.

EDO-S101 is shown to have activity in the BL1 subtype.

It is further shown that EDO-S101 has activity in wild-type BRCA-1 TNBC, as shown in the HCC1143 cell line.

Example 3

Phase 1/2 Study to Investigate the Safety, Pharmacokinetics, and Efficacy of EDO-S101, an Innovative Histone Deacetylase Alkylating Inhibition (HDACi) Fusion Molecule, in Patients With Advanced Solid Tumors Purpose

Phase 1: Determine the safety, tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of EDO-S101 as a single agent in patients with solid tumors who have progressed after at least one (1) line of conventional therapy.

Phase 2: Evaluate the efficacy of EDO-S101 in selected tumor types.

Study type: Interventional

Study Design: Intervention Model: Single Group Assignment

Masking: No masking

Main purpose: Treatment

Main outcome measures:

Phase 1: Dose escalation to maximum administered dose (MAD):

- Determine the maximum tolerated dose in an optimal infusion schedule

Phase 2: Evaluation of toxicity and response rate in selected cohorts with solid tumors:

- Confirm the recommended phase 2 dose and optimal infusion schedule in selected solid tumors - Determine the objective response rate and clinical benefit rate in selected solid tumors Secondary outcome measures:

Phase 1: Dose escalation to MAD:

- Determine the maximum plasma concentration (Cmax) of EDO-S101

Phase 2: Evaluation of toxicity and response rate in selected cohorts with solid tumors:

- Evaluate the safety and tolerability of the RP2D of the selected EDOS101 program.

- Determine progression-free survival time for patients who received RP2D on the optimal infusion schedule

- Determine overall survival for patients who received RP2D on the selected study drug administration schedule.

- Establish the minimum PK profiles of EDO-S101.

Estimated enrollment: 158

Phase 1:

Schedule A: EDO-S101, IV, 60 mg/m2 up to 150 mg/m2 day 1 and 15 of each 28-day cycle

Program B: EDO-S101, IV, 60 mg/m2 up to 150 mg/m2 day 1, 8 and 15 of each 28-day cycle

Phase 2:

RP2D and the selected program will be further investigated in patients with specific types of solid tumors: relapsed/refractory SCLC, soft tissue sarcoma, non-kit GIST, triple-negative breast, and ovarian cancers. Detailed description:

Entity EDO-S101 I, a fusion molecule of an alkylating bendamustine and an innovative histone deacetylase inhibitor (HDACi), vorinostat. This phase 1/2 study will enroll patients with solid tumors. This phase 1/2 study will enroll patients with various advanced solid tumors.

The study consists of 2 phases:

- Phase 1: Dose increase up to MAD

- Phase 2: Evaluation of toxicity and response rate in selected cohorts with solid tumors The study is designed as an open-label phase 1/2 trial of single agent EDOS101. The Phase 1 portion of the study is designed to define the MTD for two (2) dosing schedules by evaluating toxicities during dose escalation to the MAD. The Phase 2 portion of the study is designed to evaluate ORR and CBR at four (4) or six (6) months, depending on solid tumor type. Eligibility

Ages eligible for study: 18 years and older (adult, senior)

Genders eligible for study: All

Accepts healthy volunteers: No

Criteria

Inclusion criteria for the phase 1 and phase 2 parts of the study:

1. Signed informed consent.

2. patients > 18 years old at the signing of the informed consent.

3. Diagnosis of advanced or metastatic solid tumors, the disease should have progressed following at least one line of conventional therapy.

4. Patients with secondary CNS metastasis are eligible if they meet certain criteria.

5. Evaluable disease; whether measurable by imaging or informative tumor marker.

6. Discontinuation of previous anticancer therapies for at least three (3) weeks or 5 half-lives, whichever is shorter.

7. Eastern Cooperative Oncology Group (ECOG) performance status < 2

8. Neutrophils > 1,500 pl.

9. Platelets > 100,000 pl.

10. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) < 3 upper limit of normal (ULN). In cases with liver involvement ALT/AST < 5x ULN.

11. Total bilirubin < 1.5 mg/dl unless elevated due to known Gilbert syndrome.

12. Creatinine < 1.5 ULN.

13. Serum potassium within normal range.

14. If you are a woman of childbearing potential (i.e., not postmenopausal or surgically sterile), you must be willing to abstain from sexual intercourse or employ an effective barrier or medical method of contraception during study drug administration and follow-up periods. If you are male, you must be sterile or willing to abstain from sexual intercourse or use a barrier method of contraception during study treatment and for at least 6 months after the last treatment.

Exclusion criteria for the phase 1 and phase 2 parts of the study:

1. Patients with primary cancer of the central nervous system (CNS).

2. Patients with QTc interval > 450 ms for men and > 470 ms for women.

3. Patients who are being treated with drugs known to prolong the QT/QTc interval.

4. Patients who are being treated with valproic acid for any of its indications (epilepsy, mood disorder) should be excluded or should stop using the medication.

5. Any serious medical condition that interferes with compliance with study procedures. 6. History of solid tumor malignancy diagnosed within the last three (3) years of study enrollment, excluding adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer. breast cancer in situ, prostate cancer in situ (patients must have shown no evidence of active disease for 2 years prior to enrollment)

7. Pregnant or breastfeeding women.

8. New York Heart Association (NYHA) stage III/IV congestive heart failure, inadequately controlled arrhythmias, or other significant comorbidities [e.g., active infection requiring systemic treatment, history of human immunodeficiency virus infection ( HIV) or active hepatitis B or hepatitis C].

9. Use of other investigational agents within 30 days or 5 half-lives prior to the first dose of study drug. Provided the patient has recovered from any related toxicity > grade 1. 10. Steroid treatment within seven (7) days prior to study treatment. Patients requiring intermittent use of bronchodilators, topical steroids, or local steroid injections will not be excluded from the study. Patients who have been stabilized on 10 mg of oral prednisolone daily (or equivalent), daily or less seven (7) days prior to study drug administration.

Phase 2 Tumor Specific Eligibility Criteria

Phase 2 patients must meet cohort-specific inclusion/exclusion criteria in addition to the general inclusion/exclusion criteria for Phase 1 and 2 studies listed above.

Cohort 1 Patient Population: Relapsed/Refractory SCLC

1. Limited or extensive disease stage of histologically or ecologically confirmed SCLC. The disease must progress during previous treatment or relapse after it.

2. At least one line of prior combination chemotherapy that includes adequate doses of platinum compound and has progressed during therapy or after prior treatment.

3. At least 3 weeks or 5 half-lives, whichever is shorter, must have elapsed since the previous treatment provided the patient has recovered from any toxicity related to < grade 1.

4. Prior radiotherapy is acceptable as long as the patient has recovered from any acute radiotherapy-related toxicity.

Cohort 2 Patient Population: Relapsed/Refractory Non-Kit Soft Tissue Sarcoma or GIST

1. Histologically confirmed diagnosis of advanced, unresectable or metastatic soft tissue sarcoma not amenable to curative treatment with surgery or radiotherapy excluding: chondrosarcoma, neuroblastoma, osteosarcoma, embryonal rhabdomyosarcoma or Kaposi's sarcoma.

2. Must have received at least one prior first-line combination chemotherapy regimen or at least two first-line single-agent regimens. Adjuvant chemotherapy is not considered first-line unless the disease progresses within 6 months of treatment.

3. Disease must be progressive/relapsing during or after prior treatment. At least 3 weeks must have passed since the previous chemotherapy or 5 half-lives, whichever is shorter, provided the patient recovers from any related toxicity to < grade 1.

4. Presence of measurable disease as defined by the response evaluation criteria in solid tumors (RECIST 1.1, Eisenhaueret al.2009).

Cohort 3 Patient Population: Relapsed/Refractory Triple Negative Breast Cancer

1. Histologically or cytologically confirmed locally advanced or metastatic triple negative metastatic breast cancer.

2. Must have received at least one line of chemotherapy, at least 3 weeks should have passed since previous chemotherapy or 5 half-lives, whichever is shorter, provided the patient recovers from the acute toxicity of previous therapies to < grade 1.

3. Previous radiotherapy is acceptable as long as it is given within 4 weeks before starting this trial and the patient recovers from any acute radiotherapy-related toxicity.

4. Disease must be progressive/relapsing during or after prior treatment.

5. Presence of measurable disease as defined by the Response Evaluation Criteria.

Cohort 4 Patient Population: Relapsed/Refractory Ovarian Cancer

1. Histologically or cytologically confirmed advanced ovarian cancer: epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (excluding borderline ovarian cancer) that is resistant or refractory to platinum therapy.

to. Platinum-resistant ovarian cancer is defined as disease that responded to primary platinum therapy and then progressed within 6 months or disease that progressed during or within six months after completion of subsequent platinum therapy. .

b. Primary platinum-refractory disease is defined as disease that has not responded to a platinum-based regimen or has not experienced disease recurrence within 3 months of completing a first-line platinum-based regimen.

2. Disease must be progressive/relapsing during or after prior treatment. At least 3 weeks must have passed since the previous chemotherapy or 5 half-lives, whichever is shorter, provided the patient recovers from the acute toxicity of the previous therapies to < grade 1.

3. Presence of measurable disease as defined by the response evaluation criteria in solid tumors (RECIST 1.1, Eisenhaueret al.).2009).

Claims (15)

1. Tinostamustine or a pharmaceutically acceptable salt thereof for use in the treatment of triple negative breast cancer (TNBC) in a patient in need thereof, wherein tinostamustine or a pharmaceutically acceptable salt thereof is used in combination with a DNA damage response (RDA) inhibitor. 2. Tinostamustine or a pharmaceutically acceptable salt thereof for use in the treatment of TNBC according to claim 1, wherein the TNBC subtype is BL1 and/or wherein the TNBC subtype is BRCA-1 wild type. ; and where preferably, the CMTN is recurrent and/or resistant. 3. Tinostamustine or a pharmaceutically acceptable salt thereof for use in the treatment of TNBC according to claims 1 or 2, wherein the RDA inhibitor is a PARP inhibitor, wherein optionally the PARP inhibitor It's olaparib. 4. Tinostamustine or a pharmaceutically acceptable salt thereof for use in the treatment of TNBC according to any of the preceding claims, wherein the tinostamustine and the RDA inhibitor are administered concurrently, sequentially or separately. 5. Tinostamustine or a pharmaceutically acceptable salt thereof for use in the treatment of TNBC according to any of the preceding claims, wherein the tinostamustine or a pharmaceutically acceptable salt thereof is administered intravenously to the patient in need thereof. at a dosage level of 0.3 mg/m2 to 300 mg/m2 of patient body surface area, or 60 to 150 mg/m2 of patient body surface area, or 80 to 100 mg/m2 of patient's body surface area. 6. Tinostamustine or a pharmaceutically acceptable salt thereof for use in the treatment of TNBC according to any one of claims 1 to 5, wherein the tinostamustine or a pharmaceutically acceptable salt thereof is administered intravenously to the patient. You need it on days 1, 8, and 15 of a 28-day treatment cycle, or on days 1 and 15 of a 28-day treatment cycle. 7. Tinostamustine or a pharmaceutically acceptable salt thereof for use in the treatment of TNBC according to any one of claims 1 to 6, wherein the tinostamustine or a pharmaceutically acceptable salt thereof is administered intravenously to the patient. you need it for an infusion time of 60 minutes; or an infusion time of 45 minutes; or an infusion time of 30 minutes. 8. Tinostamustine or a pharmaceutically acceptable salt thereof for use in the treatment of TNBC according to any one of claims 1 to 7, wherein the tinostamustine or a pharmaceutically acceptable salt thereof is administered intravenously to the patient. needing it at a dosage level of 80 mg/m2 to 100 mg/m2 of patient body surface area, on days 1 and 15 of a 28-day treatment cycle, and for an infusion time of 60 minutes . 9. Tinostamustine or a pharmaceutically acceptable salt thereof for use in the treatment of TNBC according to any one of claims 1 to 8, wherein the patient is treated with tinostamustine or a pharmaceutically acceptable salt thereof and radiotherapy, wherein the patient who needs it preferably receives said radiotherapy treatment at a dose of 1 to 5 Gy for 5-10 consecutive days and preferably 2 Gy for 5-10 consecutive days. 10. A combination for use in the treatment of triple negative breast cancer (TNBC) comprising tinostamustine or a pharmaceutically acceptable salt thereof, and another agent(s) selected from an RDA inhibitor , where preferably, the molar ratio between tinostamustine and other agent(s) is selected from: 1:2000 to 2000:1; 1:100 to 1:2000; 1:500 to 1:1000; 1:500 to 1:900. 11. A pharmaceutical composition for use in the treatment of triple negative breast cancer (TNBC) comprising a pharmaceutically acceptable carrier and a combination according to claim 10. 12. A combination comprising tinostamustine or a pharmaceutically acceptable salt thereof, and another agent(s) selected from an RDA inhibitor, wherein the combination does not comprise a glucocorticoid, and wherein preferably, the molar ratio between tinostamustine and other agent(s) is selected from: 1:2000 to 2000:1; 1:100 to 1:2000; 1:500 to 1:1000; 1:500 to 1:900. 13. A combination comprising tinostamustine or a pharmaceutically acceptable salt thereof, and another agent(s) selected from olaparib, wherein preferably, the molar ratio between tinostamustine and other agent(s) is selected from: 1:2000 to 2000:1; 1:100 to 1:2000; 1:500 to 1:1000; 1:500 to 1:900. 14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination according to claim 12 or claim 13. 15. The combination according to claim 12 or claim 13, or the composition according to claim 14, for use as a medicament, optionally for use in the treatment of cancer in a patient in need thereof, preferably of the CMTN.